Uveal melanoma is the major intraocular cancer, with 1,500 new cases in North America per year and a 50% chance of metastasizing to the liver1,2. The majority of uveal melanomas contain mutated Gαq that is constitutively active leading to aberrant activation of the Mitogen-Activated Protein Kinase (MAPK) pathway and concomitant tumor progression3,4. Gαq directly activates the phospholipase C beta isoforms (PLC-β1-4) leading to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers mobilize intracellular calcium stores and activate protein kinase C (PKC) to promote proliferation5,6. Gαq also directly activates p63RhoGEF and related guanine nucleotide exchange factors that subsequently activate the low-molecular weight GTPase, RhoA, and possibly other, related GTPases7,8. Excessive activation of RhoA and related GTPases has also been shown to contribute to cancer progression9,10.
Melanomas are categorized into distinct subtypes—uveal, cutaneous, and acral—based on multiple criteria, including: cell morphology, gene expression patterns, metastatic potential, chemoresistance, and overall treatment regimens7,8. In contrast to uveal melanomas, cutaneous melanomas are most often driven by constitutively active N-Ras or B-Raf leading to the activation of the MAPK cascade9,10. Constitutively active Gαq is rare in cutaneous melanomas but is often found in benign blue nevi derived from cutaneous melanocytes, indicating that Gαq activates MAPK signaling in these melanocytes also3,4.
The present invention overcomes previous shortcomings in the art by providing methods and compositions for modulating the signaling activity of G-alpha-q, e.g., to treat disorders associated with aberrant signaling of G-alpha-q.